Autochthonous Liver Tumors Induce Systemic T Cell Tolerance Associated with T Cell Receptor Down-Modulation

作者：Ney, Jasmin T.; Schmidt, Thomas; Kurts, Christian; Zhou, Qi; Eckert, Dawid; Felsher, Dean W.; Schorle, Hubert; Knolle, Percy; Tueting, Thomas; Barchet, Winfried; Buettner, Reinhard; Limnier, Andreas; Guetgemann, Ines

来源：Hepatology, 2009, 49(2): 471-481.

DOI：10.1002/hep.22652

• SINUSOIDAL ENDOTHELIAL-CELLS
• ADMINISTERED ANTIGEN
• CROSS-PRESENTATION
• CANCER
• LYMPHOCYTES
• MYC
• ACTIVATION
• RESPONSES
• LEADS
• CD8

The reason the adaptive immune system fails in advanced liver tumors is largely unclear. To address this question, we have developed a novel murine model that combines c-myc-induced autochthonous tumorigenesis with expression of a cognate antigen, ovalbumin (OVA). When c-myc/OVA transgenic mice were crossed with liver-specific inducer mice, multifocal hepatocellular carcinomas co-expressing OVA developed in a tetracycline-dependent manner with a short latency and 100% penetrance. Transferred OVA-specific T cells, although infiltrating the tumor at high numbers, were hyporesponsive, as evidenced by a lack of in vivo cytotoxicity and interferon gamma production. This allowed the tumor to progress even in the presence of large numbers of antigen-specific T cells and even after vaccination (OVA+CpG-DNA). Interestingly, T cell receptor down-modulation was observed, which may explain antigen-specific hyporesponsiveness. This model is helpful in understanding liver cancer-specific mechanisms of T cell tolerance and dissection of antigen-specific and nonspecific mechanisms of immunotherapies in the preclinical phase. (HEPATOLOGY 2009;49:471-481.)

• 出版日期2009-2
• 单位华中科技大学